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Balanced autosomal translocation and double Robertsonian translocation in cases of primary amenorrhea in an Indian population
International Journal of Gynecology and Obstetrics 116 (2012) 253–257
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International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Balanced autosomal translocation and double Robertsonian translocation in cases of primary amenorrhea in an Indian population Neeraja Kopakka a, Rupa Dalvi a, Dhanlaxmi L. Shetty a, Bibhu R. Das b, Swarna Mandava a,⁎ a b
Cytogenetic Division, Super Religare Laboratories, Mumbai, India Research and Development Division, Super Religare Laboratories, Mumbai, India
a r t i c l e
i n f o
Article history: Received 20 May 2011 Received in revised form 20 September 2011 Accepted 17 November 2011 Keywords: Amenorrhea Balanced autosomal translocation Premature ovarian failure Robertsonian translocation
a b s t r a c t Objective: To assess the frequency of balanced autosomal translocations in patients with primary amenorrhea in an Indian population. Methods: Cytogenetic analysis was carried out among women referred from all parts of India for primary amenorrhea between 2002 and 2010. Clinical history and laboratory findings were taken into consideration to determine the diagnosis. G-banding with trypsin–Giemsa was performed to detect chromosome abnormalities. Results: There were 15 balanced autosomal translocations in 1100 patients. Two novel translocations were identified: 1 with mosaic pattern of X chromosome monosomy and male karyotype, together with balanced autosomal translocation of chromosomes 11 and 20 in both cell lines; and 1 with double Robertsonian translocation of chromosomes 14 and 21. Conclusion: Autosomal genes have a crucial role in reproductive development. More candidate genes need to be recognized for appropriate genetic counseling and clinical management. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Primary amenorrhea—which occurs in 1%–3% of women of reproductive age [1]—refers to the absence of both menarche and secondary sexual characteristics by the age of 14 years, or complete absence of menses by the age of 16 years despite normal development of secondary sexual characteristics. Genetic factors—in addition to endocrine disturbances, and constitutional and environmental factors— have an important role in causing primary amenorrhea [2]. It is well documented that numeric and structural rearrangements of the X chromosome contribute to the symptoms of most patients with Turner syndrome, and its variants, with primary amenorrhea [1]. Worldwide, the prevalence of chromosomal abnormalities in women with primary amenorrhea varies from 15.9% to 63.3% [2–9]. The various abnormal karyotypes observed in primary amenorrhea include Turner syndrome (which is a result of X chromosome monosomy), structural abnormalities of the X chromosome (e.g. deletion on either the long arm or the short arm), and autosomal translocation with the X chromosome [9]. Balanced autosomal translocations are rare in cases of primary amenorrhea; there are only a few
⁎ Corresponding author at: Cytogenetic Division, Super Religare Laboratories, Prime Square Building, SV Road, Goregaon (West), Mumbai 400062, India. Tel.: + 91 22 30811230; fax: + 91 22 56903865. E-mail address: [email protected] (S. Mandava).
reported cases of balanced autosomal translocation in primary amenorrhea, gonadal dysgenesis, ovarian dysgenesis, and premature ovarian failure [10,11]. The aim of the present study was to report balanced autosomal translocations in cases of primary amenorrhea—excluding numeric and structural sex chromosome abnormalities and balanced X;autosome translocations. 2. Materials and methods Cytogenetic analysis was carried out at Super Religare Laboratories, Mumbai, India, for women referred for primary amenorrhea by gynecologists from all parts of India between January 1, 2002, and December 31, 2010. Detailed clinical histories were obtained through the referring gynecologists. The Institutional Review Committee of Super Religare Laboratories approved the study. Written consent was provided by all women. In cases involving younger patients, consent was obtained from the parents/siblings. Cytogenetic analysis was performed using peripheral blood lymphocyte cultures via the modified standard protocol of Moorhead et al. [12]. A 0.5-mL sample was inoculated in 6 mL of RPMI medium supplemented with 20% fetal bovine serum and 0.2 μL of phytohemagglutinin. The culture was incubated for 72 hours in a 5% CO2 incubator; the cells were harvested using hypotonic solution, followed by chilled fixative treatment. Fixed cells were dropped on slides and stained for G-banding with trypsin–Giemsa [13]. The banded
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metaphase chromosomes were examined at a 550-band resolution. At least 20 metaphase plates were analyzed from each sample, and 3 or 4 well-spread plates were photographed and karyotyped (Ikaros; Metasystems, Altlussheim, Germany). In abnormal cases (i.e. those with abnormal chromosomal aberrations), at least 50 metaphases were evaluated.
Karyotyping revealed a double translocation with a pattern of 44, XX,rob(14;21)(q10;q10)x2 (Fig. 2). Chromosomal analysis of the patient's mother and brother revealed single Robertsonian translocations: 45,XX,rob(14;21)(q10;q10) and 45,XY,rob(14;21)(q10;q10), respectively. The father's karyotype was not available. 4. Discussion
3. Results The age of the 1100 women referred for primary amenorrhea between 2002 and 2010 ranged from 14 to 30 years (median, 23 years). The most common clinical features in cases of primary amenorrhea were poorly developed or absence of secondary sexual characteristics—notably, absence of pubic and axillary hair and poor breast development. Features such as absence of uterus and ovaries, short stature, webbing of neck, cubitus vulgaris, and hypogonadism were varied in these cases. Chromosomal analysis of the 1100 cases of primary amenorrhea revealed that the most common chromosomal abnormalities were X chromosome monosomy, 46,XY sex reversal, and structural abnormalities such as deletion on the long arm and short arm of the X chromosome, X isochromosome, and translocations involving the X chromosome. Balanced autosomal reciprocal translocations, which are very rare with a clinical history of primary amenorrhea, were observed in 15 patients (Table 1). All chromosomes were involved in the translocations, except 2, 8, 9, 19, 22, and Y. Chromosome 3 was involved in 5 cases, and chromosome 7 in 3 cases. Robertsonian translocations were involved in 2 cases. Novel chromosomal abnormalities were observed in 2 cases. The 1st involved a 19-year-old woman with features of Turner syndrome. Her height was 150 cm and she weighed 40 kg. The level of folliclestimulating hormone (FSH) was 54.3 mIU/mL and the level of thyroid-stimulating hormone was normal. Ultrasonography revealed rudimentary ovaries (31 × 6.5 mm). Chromosomal analysis revealed mos 45,X,t(11;20)(p11.2;q11.23)[46]/46,XY,t(11;20)(p11.2;q11.23) [4] (Fig. 1). The 2nd case involved a 17-year-old patient with primary amenorrhea. On examination, both ovaries were absent and the uterus was hypoplastic. The FSH level was 47.8 mIU/mL, luteinizing hormone level was 21.9 mIU/mL, and prolactin level was 8.9 ng/mL.
Genetic disorders can have a considerable health and economic impact on affected individuals, their families, and their communities. Genetic causes of amenorrhea account for approximately 45% of cases—which may be a result of, for example, gonadal dysgenesis, chromosomal disorders, or Müllerian agenesis [14]. Many studies have been undertaken to determine the frequency of sex-chromosome abnormalities among women with primary amenorrhea [2–4,8,9]. Chromosomal aberrations are present in 46%–62% of women with primary amenorrhea in the form of X aneuploidy, male karyotype, or different structural X-chromosome abnormalities such as X isochromosome, isodicentrics, rings, and deleted or inverted X chromosomes [1]. Mulye et al. [15] observed an incidence of chromosomal abnormalities of 48% in a group of hypergonadotropic patients, compared with none in a group with hypogonadotropic hypogonadism. Several studies have reported X;autosome translocations in primary amenorrhea [5,9,16]. Because most studies report the frequency of chromosome abnormalities related to sex chromosomes and X;autosome translocations, the present study investigated only balanced autosomal translocations in primary amenorrhea, which are rare in the literature. Only 10 cases of balanced autosomal translocations in primary amenorrhea and premature ovarian failure have been reported [10,11,17–21] (Table 2), whereas the present study included 15 cases of balanced autosomal reciprocal translocations causing primary amenorrhea (Table 1). In the present study, 2 cases of novel balanced autosomal translocation were observed: the 1st involved mosaic balanced autosomal translocation, with 92% of cells revealing X chromosome monosomy and 8% showing male karyotype, with balanced autosomal translocation in both cell lines; the 2nd involved double Robertsonian translocation. There are reports of single Robertsonian translocations in men and women, with the latter usually
Table 1 Balanced autosomal translocations in primary amenorrhea (n = 15). Serial No.
Age, y
Clinical history
Karyotype
1 2 3
19 18 22
46,XX,t(3;7)(q27;q34) 46,XX,t(1;3)(p36.1;p21.3) 46,XX,t(5;18)(q33;q12.2)
4 5
17 30
6
19
Primary amenorrhea Primary amenorrhea Primary amenorrhea; no breast development; scanty pubic hair; FSH, 41.1 mIU/mL; LH, 35.0 mIU/mL; estrogen, 28.9 pg/mL; progesterone, 0.6 ng/mL Uterus not visualized Primary amenorrhea; poor development of secondary sexual characteristics; uterus not visualized; small ovaries Turner syndrome; rudimentary uterus and ovaries
7 8 9
18 22 16
10 11 12 13
20 27 17 14
14 15
27 25
Primary amenorrhea Uterus and ovaries not properly developed; underdeveloped breasts Primary amenorrhea; pubic hair at Tanner stage 4; nipples underdeveloped; sparse axillary hair; uterus not visualized Short stature, uterus not visualized Primary amenorrhea; uterus not visualized Primary amenorrhea; ovaries absent; hypoplastic uterus Primary amenorrhea; secondary sexual characteristics not developed; no pubic or axillary hair Hypergonadotropic hypergonadism Primary amenorrhea; infantile uterus and ovaries
Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone.
46,XX,t(7;16)(q10;q24) 46,XX,t(7;12)(q32;q22) mos 45,X,t(11;20)(p11.2;q11.23)[46]/ 46,XY,t(11;20)(p11.2;q11.23)[4] 46,XX,t(3;19),inv(9)(p11q12) 46,XX,t(1;10)(p32;q25) 46,XX,t(11;17)(q12;p11.1) 45,XX,rob(13;14)(q10;q10) 46,XX,t(4;6)(p16;p12) 44,XX,rob(14;21)(q10;q10)x2 46,XX,t(4;12)(p16;q24.1) 46,XX,t(3;15)(q21;q24) 46,XX,t(3;11)(q23;q23)
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Fig. 1. Balanced translocation with mosaic cell line. A. 45,X,t(11;20)(p11.2;q11.23) karyotype with monosomy X and balanced translocation between chromosomes 11 and 20. B. 46,XY,t(11;20)(p11.2;q11.23) karyotype with XY female and balanced translocation between chromosomes 11 and 20.
associated a history of abortion [21,22]. In the present study, the mother and brother of the patient had single Robertsonian translocations. The double translocation could have been caused by another Robertsonian translocation received from the father (whose karyotype was not available) or the patient could have had uniparental disomy for the 14;21 translocation. Balanced autosomal translocations can have deleterious effects on gametogenesis in men and women [23]. Different phenotypes such as primary amenorrhea, secondary amenorrhea, and precocious menopause could be caused by different degrees of oocyte degeneration [24]. The balanced autosomal translocations observed in the present study might cause impairment of oogenesis, leading to primary
amenorrhea. Chromosome analysis has an important role in improving management and counseling among women with an absence of menstruation. Various candidate genes (e.g. FSHR, LHR, ATM, AIRE, GDF9, FSH, PMM2, GALT, FOXL2, INHA, and TGFB1) on autosomes may have a role in ovarian failure. Mutations of these genes might comprise a small fraction of cases of ovarian failure, which leads to the absence of menarche [25]. Thus, in women evaluated for amenorrhea and gonadal dysgenesis who have autosomal translocations, the cause may be attributed to disruption of the autosomal genes that have a crucial role in reproductive development.
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Fig. 2. 44,XX,rob(14;21)(q10;q10)x2 karyotype with double Robertsonian translocation between chromosomes 14 and 21.
Table 2 Cases of balanced autosomal translocations reported in literature. Serial No.
Karyotype
Clinical history
Reference
1 2 3
46,XX,t(6;15)(p21.3;q15) 46,XX,t(8;9)(p11.2;q12) 46,XX,t(2;15)(q32.3;q13.3) (2 cases) 45,XX,t(13;14)(q10;q10) 46,XX,t(12;14)(q14;q31) (2 cases) 46,XX,t(1;11)(q31;q25) 46,XX,t(1;8)(p31.1;q22.3) 46,XX,t(4;9)(q21;p22),t(6;10)(p25;q25),t(11;14)(q23;q32)
Ovarian failure Ovarian failure Premature ovarian failure
Tupler et al. [11] Hens et al. [17]
Premature ovarian failure Müllerian agenesis and amenorrhea
Kawano et al. [18] Kucheria et al. [19]
Gonadal dysgenesis Premature ovarian failure Primary amenorrhea
Tullu et al. [10] Wong and Lam [20] Zhao et al. [21]
4 5 6 7 8
Conflict of interest The authors have no conflicts of interest. The authors are employees of Super Religare Laboratories. All cases were referred by different physicians; there is no relationship with referring physicians. No financial or other incentives were given to the physicians or the patients.
References [1] Cortés-Gutiérrez EI, Dávila-Rodríguez MI, Vargas-Villarreal J, Cerda-Flores RM. Prevalence of chromosomal aberrations in Mexican women with primary amenorrhea. Reprod Biomed Online 2007;15(4):463–7. [2] Vijayalakshmi J, Koshy T, Kaur H, Andrea MF, Selvi R, Deepa Parvathi V, et al. Cytogenetic analysis of patients with primary amenorrhea. Int J Hum Genet 2010;10(1–3):71–6. [3] Safaie A, Vasei M, Ayatollahi H. Cytogenetic analysis of patients with primary amenorrhea in Southwest of Iran. Iran J Pathol 2010;5(3):121–5. [4] Lakhal B, Laissue P, Braham R, Elghezal H, Saâd A, Fellous M, et al. BMP15 and premature ovarian failure: causal mutations, variants, polymorphisms? Clin Endocrinol (Oxf) 2009;72(3):425–6. [5] Rosa RF, Dibi RP, Picetti Jdos S, Rosa RC, Zen PR, Graziadio C, et al. Amenorrhea and X chromosome abnormalities. Rev Bras Gynecol Obstet 2008;30(10):511–7. [6] Roy AK, Banerjee D. Cytogenetic study of primary amenorrhea. J Indian Med Assoc 1995;93(8):291–2. [7] Temoçin K, Vardar MA, Süleymanova D, Ozer E, Tanriverdi N, Demirhan O, et al. Results of cytogenetic investigation in adolescent patients with primary or secondary amenorrhea. J Pediatr Adolesc Gynecol 1997;10:86–8. [8] Ten SK, Chin YM, Noor PJ, Hassan K. Cytogenetic studies in women with primary amenorrhea. Singapore Med J 1990;31:355–9.
[9] Vasu VR, Chandra N, Santhiya ST. X;7 translocation in an Indian woman with hypergonadotropic amenorrhea—a case report. Genet Test Mol Biomarkers 2009;13(4):533–6. [10] Tullu MS, Arora P, Parmar RC, Muranjan MN, Bharucha BA. Ovarian dysgenesis with balanced autosomal translocation. J Postgrad Med 2001;47(2):113–5. [11] Tupler R, Barbierato L, Larizza D, Sampaolo P, Piovella F, Maraschio P. Balanced autosomal translocations and ovarian dysgenesis. Hum Genet 1994;94:171–6. [12] Moorhead PS, Nowell PC, Mellman WJ, Battips DM, Hungerford DA. Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Cell Res 1960;20:613–6. [13] Seabright M. A rapid banding technique for human chromosomes. Lancet 1971;2(7731):971–2. [14] Kalavathi VN, Renjini Nambiar G, Chandra N, Jayashree S, Sugunashankari P, Meena J, et al. Chromosomal abnormalities in 979 cases of amenorrhea: a review. Int J Hum Genet 2010;10(1–3):65–9. [15] Mulye V, Ambani L, Shringi M, Peter J, Motashaw N. Cytogenetic studies in primary amenorrhoea. Indian J Med Res 1983;78:53–8. [16] Bertini V, Ghirri P, Bicocchi MP, Simi P, Valetto A. Molecular cytogenetic definition of a translocation t(X;15) associated with premature ovarian failure. Fertil Steril 2010;94(3):1097.e5–8. [17] Hens L, Devroey P, Van Waesberghe L, Bonduelle M, Van Steireghem AC, Liebaers I. Chromosome studies and fertility treatment in women with ovarian failure. Clin Genet 1989;36(2):81–91. [18] Kawano Y, Narahara H, Matsui N, Miyakawa I. Premature ovarian failure associated with a Robertsonian translocation. Acta Obstet Gynecol Scand 1998;77(4): 467–9. [19] Kucheria K, Taneja N, Kinra G. Autosomal translocation of chromosomes 12q & 14q in mullerian duct failure. Indian J Med Res 1988;87:290–2. [20] Wong MS, Lam ST. Cytogenetic analysis of patients with primary and secondary amenorrhoea in Hong Kong: retrospective study. Hong Kong Med J 2005;11(4): 267–72. [21] Zhao X, Shen GM, Feng Q, Sun XG, Luo Y. Cytogenetic studies of 131 patients with primary amenorrhea (including three novel abnormal karyotypes). Yi Chuan 2008;30(8):996–1002.
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[24] Burgoyne PS, Baker TG. Perinatal oocyte loss in XO mice and its implications for the aetiology of gonadal dysgenesis in XO women. J Reprod Fertil 1985;75(2): 633–45. [25] Layman LC. BMP15—the first true ovarian determinant gene on the X-chromosome? J Clin Endocrinol Metab 2006;91(5):1673–6.
Contents lists available at SciVerse ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
Balanced autosomal translocation and double Robertsonian translocation in cases of primary amenorrhea in an Indian population Neeraja Kopakka a, Rupa Dalvi a, Dhanlaxmi L. Shetty a, Bibhu R. Das b, Swarna Mandava a,⁎ a b
Cytogenetic Division, Super Religare Laboratories, Mumbai, India Research and Development Division, Super Religare Laboratories, Mumbai, India
a r t i c l e
i n f o
Article history: Received 20 May 2011 Received in revised form 20 September 2011 Accepted 17 November 2011 Keywords: Amenorrhea Balanced autosomal translocation Premature ovarian failure Robertsonian translocation
a b s t r a c t Objective: To assess the frequency of balanced autosomal translocations in patients with primary amenorrhea in an Indian population. Methods: Cytogenetic analysis was carried out among women referred from all parts of India for primary amenorrhea between 2002 and 2010. Clinical history and laboratory findings were taken into consideration to determine the diagnosis. G-banding with trypsin–Giemsa was performed to detect chromosome abnormalities. Results: There were 15 balanced autosomal translocations in 1100 patients. Two novel translocations were identified: 1 with mosaic pattern of X chromosome monosomy and male karyotype, together with balanced autosomal translocation of chromosomes 11 and 20 in both cell lines; and 1 with double Robertsonian translocation of chromosomes 14 and 21. Conclusion: Autosomal genes have a crucial role in reproductive development. More candidate genes need to be recognized for appropriate genetic counseling and clinical management. © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction Primary amenorrhea—which occurs in 1%–3% of women of reproductive age [1]—refers to the absence of both menarche and secondary sexual characteristics by the age of 14 years, or complete absence of menses by the age of 16 years despite normal development of secondary sexual characteristics. Genetic factors—in addition to endocrine disturbances, and constitutional and environmental factors— have an important role in causing primary amenorrhea [2]. It is well documented that numeric and structural rearrangements of the X chromosome contribute to the symptoms of most patients with Turner syndrome, and its variants, with primary amenorrhea [1]. Worldwide, the prevalence of chromosomal abnormalities in women with primary amenorrhea varies from 15.9% to 63.3% [2–9]. The various abnormal karyotypes observed in primary amenorrhea include Turner syndrome (which is a result of X chromosome monosomy), structural abnormalities of the X chromosome (e.g. deletion on either the long arm or the short arm), and autosomal translocation with the X chromosome [9]. Balanced autosomal translocations are rare in cases of primary amenorrhea; there are only a few
⁎ Corresponding author at: Cytogenetic Division, Super Religare Laboratories, Prime Square Building, SV Road, Goregaon (West), Mumbai 400062, India. Tel.: + 91 22 30811230; fax: + 91 22 56903865. E-mail address: [email protected] (S. Mandava).
reported cases of balanced autosomal translocation in primary amenorrhea, gonadal dysgenesis, ovarian dysgenesis, and premature ovarian failure [10,11]. The aim of the present study was to report balanced autosomal translocations in cases of primary amenorrhea—excluding numeric and structural sex chromosome abnormalities and balanced X;autosome translocations. 2. Materials and methods Cytogenetic analysis was carried out at Super Religare Laboratories, Mumbai, India, for women referred for primary amenorrhea by gynecologists from all parts of India between January 1, 2002, and December 31, 2010. Detailed clinical histories were obtained through the referring gynecologists. The Institutional Review Committee of Super Religare Laboratories approved the study. Written consent was provided by all women. In cases involving younger patients, consent was obtained from the parents/siblings. Cytogenetic analysis was performed using peripheral blood lymphocyte cultures via the modified standard protocol of Moorhead et al. [12]. A 0.5-mL sample was inoculated in 6 mL of RPMI medium supplemented with 20% fetal bovine serum and 0.2 μL of phytohemagglutinin. The culture was incubated for 72 hours in a 5% CO2 incubator; the cells were harvested using hypotonic solution, followed by chilled fixative treatment. Fixed cells were dropped on slides and stained for G-banding with trypsin–Giemsa [13]. The banded
0020-7292/$ – see front matter © 2011 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijgo.2011.09.029
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metaphase chromosomes were examined at a 550-band resolution. At least 20 metaphase plates were analyzed from each sample, and 3 or 4 well-spread plates were photographed and karyotyped (Ikaros; Metasystems, Altlussheim, Germany). In abnormal cases (i.e. those with abnormal chromosomal aberrations), at least 50 metaphases were evaluated.
Karyotyping revealed a double translocation with a pattern of 44, XX,rob(14;21)(q10;q10)x2 (Fig. 2). Chromosomal analysis of the patient's mother and brother revealed single Robertsonian translocations: 45,XX,rob(14;21)(q10;q10) and 45,XY,rob(14;21)(q10;q10), respectively. The father's karyotype was not available. 4. Discussion
3. Results The age of the 1100 women referred for primary amenorrhea between 2002 and 2010 ranged from 14 to 30 years (median, 23 years). The most common clinical features in cases of primary amenorrhea were poorly developed or absence of secondary sexual characteristics—notably, absence of pubic and axillary hair and poor breast development. Features such as absence of uterus and ovaries, short stature, webbing of neck, cubitus vulgaris, and hypogonadism were varied in these cases. Chromosomal analysis of the 1100 cases of primary amenorrhea revealed that the most common chromosomal abnormalities were X chromosome monosomy, 46,XY sex reversal, and structural abnormalities such as deletion on the long arm and short arm of the X chromosome, X isochromosome, and translocations involving the X chromosome. Balanced autosomal reciprocal translocations, which are very rare with a clinical history of primary amenorrhea, were observed in 15 patients (Table 1). All chromosomes were involved in the translocations, except 2, 8, 9, 19, 22, and Y. Chromosome 3 was involved in 5 cases, and chromosome 7 in 3 cases. Robertsonian translocations were involved in 2 cases. Novel chromosomal abnormalities were observed in 2 cases. The 1st involved a 19-year-old woman with features of Turner syndrome. Her height was 150 cm and she weighed 40 kg. The level of folliclestimulating hormone (FSH) was 54.3 mIU/mL and the level of thyroid-stimulating hormone was normal. Ultrasonography revealed rudimentary ovaries (31 × 6.5 mm). Chromosomal analysis revealed mos 45,X,t(11;20)(p11.2;q11.23)[46]/46,XY,t(11;20)(p11.2;q11.23) [4] (Fig. 1). The 2nd case involved a 17-year-old patient with primary amenorrhea. On examination, both ovaries were absent and the uterus was hypoplastic. The FSH level was 47.8 mIU/mL, luteinizing hormone level was 21.9 mIU/mL, and prolactin level was 8.9 ng/mL.
Genetic disorders can have a considerable health and economic impact on affected individuals, their families, and their communities. Genetic causes of amenorrhea account for approximately 45% of cases—which may be a result of, for example, gonadal dysgenesis, chromosomal disorders, or Müllerian agenesis [14]. Many studies have been undertaken to determine the frequency of sex-chromosome abnormalities among women with primary amenorrhea [2–4,8,9]. Chromosomal aberrations are present in 46%–62% of women with primary amenorrhea in the form of X aneuploidy, male karyotype, or different structural X-chromosome abnormalities such as X isochromosome, isodicentrics, rings, and deleted or inverted X chromosomes [1]. Mulye et al. [15] observed an incidence of chromosomal abnormalities of 48% in a group of hypergonadotropic patients, compared with none in a group with hypogonadotropic hypogonadism. Several studies have reported X;autosome translocations in primary amenorrhea [5,9,16]. Because most studies report the frequency of chromosome abnormalities related to sex chromosomes and X;autosome translocations, the present study investigated only balanced autosomal translocations in primary amenorrhea, which are rare in the literature. Only 10 cases of balanced autosomal translocations in primary amenorrhea and premature ovarian failure have been reported [10,11,17–21] (Table 2), whereas the present study included 15 cases of balanced autosomal reciprocal translocations causing primary amenorrhea (Table 1). In the present study, 2 cases of novel balanced autosomal translocation were observed: the 1st involved mosaic balanced autosomal translocation, with 92% of cells revealing X chromosome monosomy and 8% showing male karyotype, with balanced autosomal translocation in both cell lines; the 2nd involved double Robertsonian translocation. There are reports of single Robertsonian translocations in men and women, with the latter usually
Table 1 Balanced autosomal translocations in primary amenorrhea (n = 15). Serial No.
Age, y
Clinical history
Karyotype
1 2 3
19 18 22
46,XX,t(3;7)(q27;q34) 46,XX,t(1;3)(p36.1;p21.3) 46,XX,t(5;18)(q33;q12.2)
4 5
17 30
6
19
Primary amenorrhea Primary amenorrhea Primary amenorrhea; no breast development; scanty pubic hair; FSH, 41.1 mIU/mL; LH, 35.0 mIU/mL; estrogen, 28.9 pg/mL; progesterone, 0.6 ng/mL Uterus not visualized Primary amenorrhea; poor development of secondary sexual characteristics; uterus not visualized; small ovaries Turner syndrome; rudimentary uterus and ovaries
7 8 9
18 22 16
10 11 12 13
20 27 17 14
14 15
27 25
Primary amenorrhea Uterus and ovaries not properly developed; underdeveloped breasts Primary amenorrhea; pubic hair at Tanner stage 4; nipples underdeveloped; sparse axillary hair; uterus not visualized Short stature, uterus not visualized Primary amenorrhea; uterus not visualized Primary amenorrhea; ovaries absent; hypoplastic uterus Primary amenorrhea; secondary sexual characteristics not developed; no pubic or axillary hair Hypergonadotropic hypergonadism Primary amenorrhea; infantile uterus and ovaries
Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone.
46,XX,t(7;16)(q10;q24) 46,XX,t(7;12)(q32;q22) mos 45,X,t(11;20)(p11.2;q11.23)[46]/ 46,XY,t(11;20)(p11.2;q11.23)[4] 46,XX,t(3;19),inv(9)(p11q12) 46,XX,t(1;10)(p32;q25) 46,XX,t(11;17)(q12;p11.1) 45,XX,rob(13;14)(q10;q10) 46,XX,t(4;6)(p16;p12) 44,XX,rob(14;21)(q10;q10)x2 46,XX,t(4;12)(p16;q24.1) 46,XX,t(3;15)(q21;q24) 46,XX,t(3;11)(q23;q23)
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Fig. 1. Balanced translocation with mosaic cell line. A. 45,X,t(11;20)(p11.2;q11.23) karyotype with monosomy X and balanced translocation between chromosomes 11 and 20. B. 46,XY,t(11;20)(p11.2;q11.23) karyotype with XY female and balanced translocation between chromosomes 11 and 20.
associated a history of abortion [21,22]. In the present study, the mother and brother of the patient had single Robertsonian translocations. The double translocation could have been caused by another Robertsonian translocation received from the father (whose karyotype was not available) or the patient could have had uniparental disomy for the 14;21 translocation. Balanced autosomal translocations can have deleterious effects on gametogenesis in men and women [23]. Different phenotypes such as primary amenorrhea, secondary amenorrhea, and precocious menopause could be caused by different degrees of oocyte degeneration [24]. The balanced autosomal translocations observed in the present study might cause impairment of oogenesis, leading to primary
amenorrhea. Chromosome analysis has an important role in improving management and counseling among women with an absence of menstruation. Various candidate genes (e.g. FSHR, LHR, ATM, AIRE, GDF9, FSH, PMM2, GALT, FOXL2, INHA, and TGFB1) on autosomes may have a role in ovarian failure. Mutations of these genes might comprise a small fraction of cases of ovarian failure, which leads to the absence of menarche [25]. Thus, in women evaluated for amenorrhea and gonadal dysgenesis who have autosomal translocations, the cause may be attributed to disruption of the autosomal genes that have a crucial role in reproductive development.
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Fig. 2. 44,XX,rob(14;21)(q10;q10)x2 karyotype with double Robertsonian translocation between chromosomes 14 and 21.
Table 2 Cases of balanced autosomal translocations reported in literature. Serial No.
Karyotype
Clinical history
Reference
1 2 3
46,XX,t(6;15)(p21.3;q15) 46,XX,t(8;9)(p11.2;q12) 46,XX,t(2;15)(q32.3;q13.3) (2 cases) 45,XX,t(13;14)(q10;q10) 46,XX,t(12;14)(q14;q31) (2 cases) 46,XX,t(1;11)(q31;q25) 46,XX,t(1;8)(p31.1;q22.3) 46,XX,t(4;9)(q21;p22),t(6;10)(p25;q25),t(11;14)(q23;q32)
Ovarian failure Ovarian failure Premature ovarian failure
Tupler et al. [11] Hens et al. [17]
Premature ovarian failure Müllerian agenesis and amenorrhea
Kawano et al. [18] Kucheria et al. [19]
Gonadal dysgenesis Premature ovarian failure Primary amenorrhea
Tullu et al. [10] Wong and Lam [20] Zhao et al. [21]
4 5 6 7 8
Conflict of interest The authors have no conflicts of interest. The authors are employees of Super Religare Laboratories. All cases were referred by different physicians; there is no relationship with referring physicians. No financial or other incentives were given to the physicians or the patients.
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